FDA Approval for Oxaliplatin
- Approved for adjuvant therapy for stage III colorectal cancer
- Approved for initial therapy of advanced colorectal cancer
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.resection of the primary tumor. Approval is based on an improvement in disease-free survival (DFS), with no demonstrated benefit in overall survival after a median follow-up of four years.
Safety and efficacy were demonstrated in a multicenter, randomized, open-label, international clinical trial. There were 2,246 patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor, that were equally randomized to one of two arms: oxaliplatin plus infusional 5FU/LV (FOLFOX 4 regimen) and infusional 5FU/LV (De Gramont regimen). Treatment was administered every two weeks for 12 cycles (6 months).
At a median follow-up of four years, there was a statistically significant improvement in the primary endpoint of DFS for the oxaliplatin combination compared to infusional 5FU/LV, both in the overall study population (four year DFS: 76 percent vs. 69 percent hazard ratio = 0.76, 95 percent CI: 0.65, 0.90; p=0.0008) and in the subgroup with stage III disease (four year DFS: 70 percent vs. 61 percent; hazard ratio = 0.75, 95 percent CI: 0.62, 0.90; p=0.002; N=1347). Survival data were not mature at the time of the analysis with a median follow-up of 47 months. No statistical difference in overall survival was shown between the treatment arms in the overall study population (hazard ratio 0.89, 95 percent CI: 0.72, 1.09; p=0.236) or in stage III patients. No statistical difference was observed either in DFS or survival in stage II patients.
The incidence of grade 3 or grade 4 events was 70 percent and 31 percent on the oxaliplatin combination arm and infusional 5FU/LV arm, respectively. Granulocytopenia, paresthesia, diarrhea, vomiting and nausea were the most common grade 3 or 4 adverse events. Paresthesia was seen in 92 percent of patients on the oxaliplatin combination; 21 percent had residual paresthesia at 18 month follow-up. Three percent and 0.5 percent had grade 2 and 3 paresthesias, respectively, at 18 month follow-up.
Grade 3 or 4 hypersensitivity was noted in 3 percent and may require discontinuation of therapy. Hepatotoxicity (damaging effects on the liver), evidenced by increase in transaminases (57 percent vs. 34 percent) and alkaline phosphatases (42 percent vs. 20 percent), was observed more commonly in the oxaliplatin combination arm. The incidence of increased bilirubin was similar on both arms. Hepatic vascular disorders should be considered and investigated if abnormal liver function tests or portal hypertension (increased pressure in the vein connecting the vein connecting the intestines and the liver) are present and can not be explained by liver metastases or other known etiologies.
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Oxaliplatin previously received accelerated approval on August 9, 2002, for use in combination with infusional 5-FU/LV for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed during or within six months of completion of first-line therapy with the combination of bolus 5-FU/LV and irinotecan.
Safety and efficacy were demonstrated in one multicenter, randomized controlled clinical trial sponsored by the National Cancer Institute as an inter-group study led by the North Central Cancer Treatment Group. The study had seven arms at different times during its conduct, four of which were closed either due to changes in the standard of care, toxicity, or simplification.
During the study, the control arm was changed to irinotecan plus bolus 5-FU/LV. The oxaliplatin + infusional FU/LV regimen was compared to an approved control regimen of irinotecan plus bolus 5-FU/LV in 531 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. Patients may have received adjuvant therapy for resected stage II or III disease without recurrence within 12 months. After completion of enrollment, the dose of irinotecan plus 5-FU/LV was decreased due to toxicity.
The oxaliplatin + infusional FU/LV regimen showed superior survival to the irinotecan plus bolus FU/LV regimen with median survivals of 19.4 and 14.6 months (p=0.0001), respectively. Time to tumor progression and tumor response rate were also superior on the oxaliplatin + infusional FU/LV regimen.
Fatigue, neuropathy, nausea, vomiting, diarrhea, stomatitis, neutropenia, and thrombocytopenia were the more common adverse events. Febrile neutropenia or requirement for platelet transfusion were not increased as compared to the irinotecan + bolus 5-FU/LV.
Oxaliplatin has been associated with pulmonary fibrosis (<1 percent of study patients), which may be fatal. There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received oxaliplatin plus 5-FU/LV while on anticoagulants. Patients requiring oral anticoagulants may require closer monitoring.
Hypersensitivity has been observed (<2 percent Grade 3/4) in clinical studies and was usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and may require discontinuation of therapy.
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This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.